This revised proposal is being submitted as an investigator-initiated R01 application to the National Institute on Aging. There is considerable evidence from animal research that chronic exposure to high levels of adrenal corticosteroids causes atrophy of the hippocampus and contributes to age-related declines in memory. In humans, evidence suggests that similar adverse effects may accompany excess cortisol (C) exposure. The long term goal of this research is to investigate the possible consequences of variability among and within individuals in rates of change in endogenous C concentrations on cognitive and neural outcomes. The specific aims of our proposal are to evaluate the impact of long term cortisol concentration on i) risk for dementia ii) risk for cognitive decline iii) rates of change in regional brain volumes iv) rates of change in regional cerebral blood flow v) brain activation during spatial navigation. Our central hypothesis is that levels of C will be associated with increased risk for dementia, increased risk for cognitive decline and increased risk for neural dysfunction in the hippocampus and pre-frontal cortex. We plan to evaluate the influence of endogenous C measures on these neural outcomes by analysis of existing data from the Baltimore Longitudinal Study of Aging (BLSA). In this dataset, we have access to urine samples from BLSA participants spanning a time interval of up to 30 years. Immunoenzymatic assay of existing urine samples will allow determination of C levels as well as rates of C increases and/or decreases within and between individuals. Cortisol values will be used as the primary predictor in mixed model regression analyses of our cognitive and neural outcomes. Our primary outcome measures include diagnoses of dementia as well as cognitive assessments. In addition, a subset of BLSA participants have received brain MRI and PET scans (N = 158) for assessment of brain structure and function, respectively. In addition to the analysis of existing data, we propose an ancillary study. We propose to select 2 groups of subjects based on their history of C exposure for participation in a functional MRI assessment of spatial navigation. The proposed research is significant in that it that it will allow us to identify a putative risk factor for age-related declines in both cognitive and neural function and ultimately lead to possible treatment strategies to ameliorate or delay cognitive and neural dysfunction. [unreadable] [unreadable] [unreadable]